Nutritional adequacy of goat milk infant formulas for term infants: a double-blind randomised controlled trial.
The safety and nutritional adequacy of goat milk infant formulas have been questioned. The primary aim of the present study was to compare the growth and nutritional status of infants fed a goat milk infant formula with those of infants fed a typical whey-based cow milk infant formula. The secondary aim was to examine a range of health- and allergy-related outcomes. A double-blind, randomised controlled trial with 200 formula-fed term infants randomly assigned to receive either goat or cow milk formula from 2 weeks to at least 4 months of age was conducted. A cohort of 101 breast-fed infants was included for comparison. Weight, length and head circumference were measured at 2 weeks and 1, 2, 3, 4, 6 and 12 months of age. Nutritional status was assessed from serum albumin, urea, creatinine, Hb, ferritin, and folate and plasma amino acid concentrations at 4 months. Z-scores for weight, length, head circumference and weight for length were not different between the two formula-fed groups. There were differences in the values of some amino acids and blood biomarkers between the formula-fed groups, but the mean values for biomarkers were within the normal reference range. There were no differences in the occurrence of serious adverse events, general health, and incidence of dermatitis or medically diagnosed food allergy. The incidence of parentally reported blood-stained stools was higher in the goat milk formula-fed group, although this was a secondary outcome and its importance is unclear. Goat milk formula provided growth and nutritional outcomes in infants that did not differ from those provided by a standard whey-based cow milk formula.


Purpose in life as a resource for increasing comfort with ethnic diversity.
Emerging demographic trends signal that White Americans will soon relinquish their majority status. As Whites' acclimation to an increasingly diverse society is poised to figure prominently in their adjustment, identifying sources of greater comfort with diversity is important. Three studies (N = 519) revealed evidence that purpose in life bolsters comfort with ethnic diversity among White adults. Specifically, dispositional purpose was positively related to diversity attitudes and attenuated feelings of threat resulting from viewing demographic projections of greater diversity. In addition, when primed experimentally, purpose attenuated participants' preferences for living in an ethnically homogeneous-White city, relative to a more diverse city when shown maps displaying ethno-demographic information. These effects persisted after controlling for positive affect and perceived connections to ethnic out-groups, suggesting the robust influence of purpose. Potential benefits of situating purpose as a unique resource for navigating an increasingly diverse society are discussed.


Mechanism of action of carbocyclic thromboxane A2 and its interaction with prostaglandin I2 and verapamil in isolated arteries.
Carbocyclic thromboxane A2 (10(-9) to 10(-7) M) produced a concentration-dependent contraction of helical strips of dog cerebral, coronary, mesenteric, renal, and femoral arteries and of monkey cerebral, coronary, and mesenteric arteries. Contraction induced by low concentrations of carbocyclic thromboxane A2 tended to be greater in cerebral arterial strips. Even after 60 minutes of exposure to Ca++-free media, approximately one-half of the contractile response of dog cerebral and mesenteric arteries to 10(-8) M carbocyclic thromboxane A2 was retained. The contractile response was attenuated by diphloretin phosphate, a prostaglandin antagonist, and was potentiated by aspirin. In dog cerebral arterial strips contracted with carbocyclic thromboxane, the relaxant response to prostaglandin I2 was less than the response seen in mesenteric and coronary arteries, whereas, in contrast, the response to verapamil was greater in cerebral arteries. Concentration-relaxation curves for papaverine did differ appreciably. It may be concluded that contractions induced by carbocyclic thromboxane are associated with the release of Ca++ from intracellular storage sites and, in addition, the increase in transmembrane Ca++ influx. Greater susceptibility of cerebral arteries to verapamil may indicate that the Ca++ antagonist is of use to relieve the persistent contraction of cerebroarterial smooth muscle. Prostaglandin I2 appears to counteract effectively the action of potent vasoconstrictors, such as thromboxane A2 and its carbocyclic analog, in various vascular beds.


Simultaneous clustering of multiple gene expression and physical interaction datasets.
Many genome-wide datasets are routinely generated to study different aspects of biological systems, but integrating them to obtain a coherent view of the underlying biology remains a challenge. We propose simultaneous clustering of multiple networks as a framework to integrate large-scale datasets on the interactions among and activities of cellular components. Specifically, we develop an algorithm JointCluster that finds sets of genes that cluster well in multiple networks of interest, such as coexpression networks summarizing correlations among the expression profiles of genes and physical networks describing protein-protein and protein-DNA interactions among genes or gene-products. Our algorithm provides an efficient solution to a well-defined problem of jointly clustering networks, using techniques that permit certain theoretical guarantees on the quality of the detected clustering relative to the optimal clustering. These guarantees coupled with an effective scaling heuristic and the flexibility to handle multiple heterogeneous networks make our method JointCluster an advance over earlier approaches. Simulation results showed JointCluster to be more robust than alternate methods in recovering clusters implanted in networks with high false positive rates. In systematic evaluation of JointCluster and some earlier approaches for combined analysis of the yeast physical network and two gene expression datasets under glucose and ethanol growth conditions, JointCluster discovers clusters that are more consistently enriched for various reference classes capturing different aspects of yeast biology or yield better coverage of the analysed genes. These robust clusters, which are supported across multiple genomic datasets and diverse reference classes, agree with known biology of yeast under these growth conditions, elucidate the genetic control of coordinated transcription, and enable functional predictions for a number of uncharacterized genes.


Aging and the passage of L-tyrosine, L-DOPA, and inulin into mouse brain slices in vitro.
The effect of age on active transport of catecholamine precursors was studied in a healthy population of mature (12-mo.-old) and senescent (30-mo.-old) C57BL/6J male mice. No age differences were observed in uptake of L-(3H)-tyrosine IN VITRO by slices of hypothalamus, brain stem, and striatum at external concentrations equal to or greater than blood levels. However, age-related reductions were observed intermittently in the hypothalamus, brain stem, and striatum at very low concentrations of tyrosine (less than 10 pg/ml). No age differences were observed in incorporation of L-(3H)-tyrosine into hypothalamic proteins when corrected for intracellular uptake of L-(3H)-tyrosine. No age differences were observed in uptake of L-(3H)-DOPA. The possible contribution of age-related changes in extra-cellular space to decreased uptake was determined to be negligible by wash-out studies of tyrosine and by the uptake of inulin. A significant age-related increase of inulin uptake IN VITRO was observed under ionic conditions which minimize tissue swelling.


Natural variability contributes to model-satellite differences in tropical tropospheric warming.
A long-standing discrepancy exists between general circulation models (GCMs) and satellite observations: The multimodel mean temperature of the midtroposphere (TMT) in the tropics warms at approximately twice the rate of observations. Using a large ensemble of simulations from a single climate model, we find that tropical TMT trends (1979-2018) vary widely and that a subset of realizations are within the range of satellite observations. Realizations with relatively small tropical TMT trends are accompanied by subdued sea-surface warming in the tropical central and eastern Pacific. Observed changes in sea-surface temperature have a similar pattern, implying that the observed tropical TMT trend has been reduced by multidecadal variability. We also assess the latest generation of GCMs from the Coupled Model Intercomparison Project Phase 6 (CMIP6). CMIP6 simulations with muted warming over the central and eastern Pacific also show reduced tropical tropospheric warming. We find that 13% of the model realizations have tropical TMT trends within the observed trend range. These simulations are from models with both small and large climate sensitivity values, illustrating that the magnitude of tropical tropospheric warming is not solely a function of climate sensitivity. For global averages, one-quarter of model simulations exhibit TMT trends in accord with observations. Our results indicate that even on 40-y timescales, natural climate variability is important to consider when comparing observed and simulated tropospheric warming and is sufficiently large to explain TMT trend differences between models and satellite data.


Peptide ligands stabilized by small molecules.
Bicyclic peptides generated through directed evolution by using phage display offer an attractive ligand format for the development of therapeutics. Being nearly 100-fold smaller than antibodies, they promise advantages such as access to chemical synthesis, efficient diffusion into tissues, and needle-free application. However, unlike antibodies, they do not have a folded structure in solution and thus bind less well. We developed bicyclic peptides with hydrophilic chemical structures at their center to promote noncovalent intramolecular interactions, thereby stabilizing the peptide conformation. The sequences of the peptides isolated by phage display from large combinatorial libraries were strongly influenced by the type of small molecule used in the screen, thus suggesting that the peptides fold around the small molecules. X-ray structure analysis revealed that the small molecules indeed formed hydrogen bonds with the peptides. These noncovalent interactions stabilize the peptide-protein complexes and contribute to the high binding affinity.


Positive adaptations to weight-lifting training in the elderly.
Maximal weight-lifting performance, isometric strength, isokinetic torque, whole muscle and individual fiber cross-sectional areas, and muscle evoked contractile properties were assessed in 14 elderly males before and after 12 wk of weight-lifting training. Dynamic elbow flexion training of one arm resulted in a significant 48% mean increase in the maximal load that could be lifted once (1 RM) and a smaller improvement in isokinetic torque (8.8%) but no change in isometric strength. In the contralateral control arm, 1 RM and isokinetic torque increased by 12.7 and 6.5%, respectively, but isometric strength did not change. The interpolated twitch technique confirmed complete motor unit activation during a maximal isometric contraction of the elbow flexors before and after the training. Bilateral leg press training effected mean increases of 17 and 23% in isokinetic torque and dynamic lifting capacity, respectively. The mean maximal cross-sectional area of the elbow flexors (biceps brachii and brachialis) increased by 17.4% in the trained arm but did not change the control arm. The increase in the mean area of type II fibers in the biceps brachii muscle in the trained arm (30.2%) was greater than the corresponding change in the control arm (10.7%, P less than 0.05). The most significant change in the evoked contractile properties of the trained elbow flexors was the increase in twitch half-relaxation time. It is concluded that older individuals retain the potential for significant increases in strength performance and upper limb muscle hypertrophy in response to overload training.


Nano-mole scale side-chain signal assignment by 1H-detected protein solid-state NMR by ultra-fast magic-angle spinning and stereo-array isotope labeling.
We present a general approach in 1H-detected 13C solid-state NMR (SSNMR) for side-chain signal assignments of 10-50 nmol quantities of proteins using a combination of a high magnetic field, ultra-fast magic-angle spinning (MAS) at ~80 kHz, and stereo-array-isotope-labeled (SAIL) proteins [Kainosho M. et al., Nature 440, 52-57, 2006]. First, we demonstrate that 1H indirect detection improves the sensitivity and resolution of 13C SSNMR of SAIL proteins for side-chain assignments in the ultra-fast MAS condition. 1H-detected SSNMR was performed for micro-crystalline ubiquitin (~55 nmol or ~0.5mg) that was SAIL-labeled at seven isoleucine (Ile) residues. Sensitivity was dramatically improved by 1H-detected 2D 1H/13C SSNMR by factors of 5.4-9.7 and 2.1-5.0, respectively, over 13C-detected 2D 1H/13C SSNMR and 1D 13C CPMAS, demonstrating that 2D 1H-detected SSNMR offers not only additional resolution but also sensitivity advantage over 1D 13C detection for the first time. High 1H resolution for the SAIL-labeled side-chain residues offered reasonable resolution even in the 2D data. A 1H-detected 3D 13C/13C/1H experiment on SAIL-ubiquitin provided nearly complete 1H and 13C assignments for seven Ile residues only within ~2.5 h. The results demonstrate the feasibility of side-chain signal assignment in this approach for as little as 10 nmol of a protein sample within ~3 days. The approach is likely applicable to a variety of proteins of biological interest without any requirements of highly efficient protein expression systems.


Informal payment for health care and the theory of 'INXIT'.
Informal payments are known to be widespread in the post-communist health care systems of Central and Eastern Europe. However, their role and nature remains contentious, with the debate characterized by much polemic. This paper steps back from this debate to examine the theoretical basis for understanding the persistence of informal payments. The authors develop a cognitive behavioural model of informal payment, which draws on the theory of government failure and extends Hirschman's theory of 'exit, voice, loyalty', the behavioural responses to 'decline in firms, organizations and states'. It is argued that informal payment represents another possible behavioural reaction: 'inxit', which becomes important when the channels of exit and voice are blocked. The theory is applied to explain informal payments in Hungary, but can be shown to be relevant to other countries facing similar issues. The paper examines the proposed policies to tackle informal payments, and on the basis of the theory of 'inxit' it advocates that solutions should contain an appropriate balance between exit and voice to optimize the chances of maintaining a good standard of public services.


The frequency of cognitive impairment in patients with anxiety, depression, and bipolar disorder: an unaccounted source of variance in clinical trials.
Patients with anxiety, depression, and bipolar disorder are known to be impaired relative to healthy controls on neurocognitive tests, but the degree of impairment may be obscured if the data are analyzed in terms of group means. Patients and controls were administered a comprehensive neurocognitive assessment that measured performance in 5 domains: memory, psychomotor speed, reaction time, attention, and cognitive flexibility. Clinic patients diagnosed per DSM-IV-TR criteria with generalized anxiety disorder (N = 63), major depressive disorder (N = 285), and bipolar I or II disorder (N = 96) were compared with 907 controls. Subjects' age range was 18 to 65 years. Patients had no comorbid psychiatric disorders and no medical, neurologic, or developmental conditions that might affect cognition (e.g., attention-deficit/hyperactivity disorder, brain injury, mild cognitive impairment, chronic pain). Data on patients and controls (collected from March 2003 through February 2007) were taken from a clinical database that also contained neurocognitive test scores. There were small differences between patients and controls, between different patient groups, and between treated and untreated patients when neurocognitive results in terms of group means were compared. Comparisons of results in terms of the frequency with which patients and controls fell below certain cutoff scores amplified the importance of these differences. Only 4% of controls fell below a standard score of 70 (2 standard deviations below the mean) on 2 or more cognitive domains, but 19% of anxiety patients, 21% of depressed patients, and 30% of bipolar patients fell below the standard score. Substantial numbers of patients with anxiety, depression, and bipolar disorder are cognitively impaired. A score that is 2 standard deviations below the mean is usually clinically important, and 2 domain scores in that range is cause for serious concern. The importance of this finding is discussed, with respect to clinical trials, in terms of establishing a homogeneous trial population and minimizing the placebo response rate.


Changing trends in gastrointestinal disease in the Asia-Pacific region.
The new millennium has seen distinct changes in the pattern of gastrointestinal disease in the Asia-Pacific region. These changes are important as more than half of the world's population come from the region and therefore impact significantly on the global disease burden. The highest incidence of gastric cancer (GCA) has been reported from Asia and GCA remains a very important cancer. However time-trend studies have shown a decrease in GCA incidence in several countries in Asia. A rise in cardio-esophageal cancers as seen in the West has not been reported. On the other hand, colorectal cancer has been steadily increasing in Asia with age-standardized incidence rates of some countries approaching that of the West. The pattern of acid-related diseases has also changed. Gastroesophageal reflux disease is a fast emerging disease with an increasing prevalence of reflux esophagitis and reflux symptoms. The prevalence of peptic ulcer disease has at the same time declined in step with a decrease in H. pylori infection. Many of the changes taking place mirror the Western experience of several decades ago. Astute observation of the epidemiology of emerging diseases combined with good scientific work will allow a clearer understanding of the key processes underlying these changes. With rapid modernization, lifestyle changes have been blamed for an increase in several diseases including gastroesophageal reflux disease, nonalcoholic fatty liver disease and colorectal cancer. A worrying trend has been the increase in obesity among Asians, which has been associated with an increase in metabolic diseases and various gastrointestinal cancers. Conversely, an improvement in living conditions has been closely linked to the decrease in GCA and H. pylori prevalence.


[Prediabetes, becoming the equivalent of coronary artery disease].
Prediabetes refers to a state where blood glucose levels are higher than normal, but not high enough to meet the diagnostic criteria for diabetes mellitus. Similar to the worldwide trend, data derived from large studies has shown an increasing trend in the prevalence of prediabetes in Turkey. According to the Centers for Disease Control and Prevention data, 79 million individuals in the United States have prediabetes. This implies a large population worldwide is at risk of developing diabetes in the near future. In addition to its strong association with the development of diabetes, prediabetes itself represents an increased risk of developing cardiovascular disease and its complications. This review will focus on definition, detection, association with cardiovascular disease and treatment of prediabetes.


N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats.
Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes. Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-α (all P<0.05 vs. C). NAC but not ALP increased cardiac APN concentrations and AdipoR2 expression in diabetic rats. ALP enhanced the effects of NAC in restoring cardiac AdipoR2 and phosphorylation of Akt, STAT3 and eNOS in diabetic rats. Further, NAC and ALP, respectively, decreased postischemic myocardial infarct size and creatinine kinase-MB (CK-MB) release in diabetic rats, while their combination conferred synergistic protective effects. In addition, exposure of cultured rat cardiomyocytes to high glucose resulted in significant reduction of cardiomyocyte APN concentration and AdipoR2 protein expression. APN supplementation restored high glucose induced AdipoR2 reduction in cardiomyocytes. NAC and ALP synergistically restore myocardial APN and AdipoR2 mediated eNOS activation. This may represent the mechanism through which NAC and ALP combination greatly reduces MI/R injury in early diabetic rats.


Dendritic structure of single hippocampal neurons according to sex and hemisphere of origin in middle-aged and elderly human subjects.
The organization of basilar dendritic patterns in the CA1 hippocampal region obtained from 13 middle-aged and elderly human subjects was assessed using the Golgi method. Neurons were classified according to hemisphere of origin and the sex of the respective subjects. Three parameters were measured: total dendritic length (TDL), number of dendritic segments (NDS) and average segment length (ASL, which is TDL divided by NDS). Dendritic segments were classified into proximal (first to third order) and distal (fourth order and above). Sex differences were found in distal TDL and in proximal and distal NDS, neurons belonging to males having larger values than those belonging to females. In addition, a hemispheric difference was detected in distal TDL, in which neurons of the left hemisphere had larger values than those of the right hemisphere.


Plasma biomarkers in pediatric patients undergoing cardiopulmonary bypass.
It is critical to identify at-risk patients and minimize the deleterious effects of cardiopulmonary bypass (CPB) procedures in pediatric populations. The present study screened the plasma proteome of pediatric patients undergoing CPB procedures to identify potential clinical biomarkers related to tissue damage, inflammation, or other pathologies. Blood samples were collected at five different time points from 10 children undergoing a CPB procedure. Plasma was isolated and analyzed using two-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption ionization time of flight mass spectrometry. Levels of differentially regulated proteins identified by two-dimensional differential in-gel electrophoresis, and related proteins were then measured in all time points and patients. As well, associated small molecules and ions were measured. The present study identified 13 proteins and protein isoforms altered in expression, including hemopexin, ceruloplasmin, inter-alpha inhibitor H4, and alpha-2-macroglobulin. Immunoblot analysis revealed significant decreases in each of these proteins during the CPB procedure. Significant changes in the levels of copper, iron, Hb, epinephrine, norepinephrine, and serotonin were observed. The potential markers of pathology (inflammation, oxidative stress) identified during this preliminary study may illuminate opportunities for preventative measures and/or treatments during and following CPB procedures in pediatric patients.


Transforming growth factor-beta is involved in the pathogenesis of dialysis-related amyloidosis.
Advanced glycation end product-modified beta2-microglobulin (AGE-beta2m) is an important component of dialysis-related amyloidosis (DRA). Its presence induces monocyte chemotaxis and the release of the proinflammatory cytokines through macrophage activation. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that also has chemotactic activity for monocytes at very low (0.1 to 10 pg/mL) concentrations and inhibits proinflammatory cytokine production of macrophages. In this study, we investigated the role of TGF-beta in the pathogenesis of DRA. We performed an immunohistochemical study of DRA tissues (8 cases) to confirm the existence of TGF-betas and their receptors; we also performed a chemotaxis assay of human monocytes as well as enzyme-linked immunosorbent assay (ELISA) of TGF-beta1, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-1 receptor antagonist (IL-1Ra) in the supernatant of human monocyte-derived macrophage cell culture under varying conditions of incubation with TGF-beta1, AGE-beta2m, and TGF-beta1 antibody additions. There was positive staining for TGF-betas (types 1, 2, and 3) and their receptors (types I, II, and III) in infiltrated macrophages (CD68+), synovial lining cell, as well as vascular walls around amyloid deposition. AGE-beta2m also induced TGF-beta1 production by macrophages in a dose-dependent manner (410 +/- 80 pg/mL at 12.5 microg/mL, 621 +/- 62 pg/mL at 25 microg/mL, and 776 +/- 62 pg/mL at 50 microg/mL of AGE-beta2m). AGE-beta2m induced significant TNF-alpha and IL-1Ra production by macrophage. The addition of exogenous TGF-beta1 (0.1 to 10 ng/mL) decreased AGE-beta2m-induced TNF-alpha production and increased IL-1Ra production in a dose-dependent fashion. IL-1beta production was not effected by any experimental conditions. In chemotaxis assay, anti-TGF-beta1 antibody (0.1 to 10 microg/mL) attenuated AGE-beta2m-induced monocyte chemotaxis. These results provide the first evidence to our knowledge for the presence of TGF-beta in DRA tissue, as well as the stimulatory action of AGE-beta2m on tissue macrophages. In turn, TGF-beta suppresses the proinflammatory activation of macrophages, suggesting a dual role for TGF-beta in the inflammatory process of DRA. These observations may provide a pathophysiologic link between TGF-beta and DRA.


A reiterative mode of DNA synthesis adopted by HIV-1 reverse transcriptase after a misincorporation.
Amplification of oligonucleotide repeats is a major cause of variability and instability of genomes. This phenomenon is probably due to an aberration in the copying process of polymerases. We show here that in the presence of MnCl2, mismatch formation commits HIV-1 reverse transcriptase to a new mode of DNA synthesis which generates repetitive products. This activity is distinct from terminal transferase since it requires specific DNA motifs in the template. This mechanism, which is processive, also works on homologous RNA templates where it generates reiterative products more than 150 nucleotides long. The corresponding mechanism, which involves extensive primer misalignment, is strikingly similar to that postulated for telomerases.


Effect of temperature and hydrophilic ratio on the structure of poly(N-vinylcaprolactam)-block-poly(dimethylsiloxane)-block-poly(N-vinylcaprolactam) polymersomes.
Nanosized polymeric vesicles (polymersomes) assembled from ABA triblock copolymers of poly(N-vinylcaprolactam)-poly(dimethylsiloxane)-poly(N-vinylcaprolactam) (PVCL-PDMS-PVCL) are a promising platform for biomedical applications, as the temperature-responsiveness of the PVCL blocks enables reversible vesicle shrinkage and permeability of the polymersome shell at elevated temperatures. Herein, we explore the effects of molecular weight, polymer block weight ratios, and temperature on the structure of these polymersomes via electron microscopy, dynamic light scattering, small angle neutron scattering (SANS), and all-atom molecular dynamic methods. We show that the shell structure and overall size of the polymersome can be tuned by varying the hydrophilic (PVCL) weight fraction of the polymer: at room temperature, polymers of smaller hydrophilic ratios form larger vesicles that have thinner shells, whereas polymers with higher PVCL content exhibit interchain aggregation of PVCL blocks within the polymersome shell above 50 °C. Model fitting and model-free analysis of the SANS data reveals that increasing the mass ratio of PVCL to the total copolymer weight from 0.3 to 0.56 reduces the temperature-induced change in vesicle diameter by a factor of 3 while simultaneously increasing the change in shell thickness by a factor of 1.5. Finally, by analysis of the shell structures and overall size of polymersomes with various PVCL weight ratios and those without temperature-dependent polymer components, we bring into focus the mechanism of temperature-triggered drug release reported in a previous study. This work provides new fundamental perspectives on temperature-responsive polymersomes and elucidates important structure-property relationships of their constituent polymers.


Influence of cocaine, ethanol, or their combination on epicardial coronary arterial dimensions in humans.
Cocaine and ethanol are often abused concomitantly, and this combination may be more lethal than either substance alone. Although previous studies showed that cocaine causes coronary arterial vasoconstriction, the combined effect of cocaine and ethanol on the coronary vasculature in humans is unknown. Thus, we assessed the effects of intranasal cocaine, intravenous ethanol, or a cocaine-ethanol combination on heart rate, systemic arterial pressure, and coronary arterial dimensions in humans. Thirty-four subjects with chest pain (27 men and seven women, aged 34 to 67 years) who were referred for catheterization received one of the following pharmacologic interventions: (1) intranasal (2 mL) and intravenous (5 mL/kg) saline (n = 8 [group A]); (2) intranasal cocaine (2 mg/kg) and intravenous saline (5 mL/kg) (n = 9 [group B]); (3) intranasal saline (2 mL) and intravenous 10% ethanol (5 mL/kg) (n = 9 [group C]); or (4) intranasal cocaine (2 mg/kg) and intravenous 10% ethanol (5 mL/kg) (n = 8 [group D]). Heart rate, systemic arterial pressure, left coronary arterial dimensions (by computer-assisted quantitative angiography), as well as blood cocaine, ethanol, and cocaine metabolite concentrations were measured before and 30, 60, and 90 minutes after initiation of the intravenous infusions. No hemodynamic or angiographic changes were observed in the group A (saline) subjects. In the group B (cocaine) subjects, the heart rate-systolic arterial pressure product increased by 5% and 10% at 30 and 90 minutes, respectively, and coronary arterial diameter decreased by 14% at these times. In the group C (ethanol) subjects, no hemodynamic changes were noted, but coronary arterial diameters increased by 12%, 11%, and 12% at 30, 60, and 90 minutes, respectively. In the group D (cocaine-ethanol) patients, rate-pressure product increased by 17%, 10%, and 16%, and coronary arterial diameters increased by 7%, 12%, and 13%, at 30, 60, and 90 minutes, respectively. The combination of intranasal cocaine and intravenous ethanol causes an increase in the determinants of myocardial oxygen demand. However, it also causes a concomitant increase in epicardial coronary arterial diameter.


Geographic access to health care services: the case of maintenance hemodialysis.
A longitudinal study of the system for delivering maintenance hemodialysis services in St Louis, Missouri was conducted to determine the significance of geographic access in the selection and continued utilization of a treatment facility. Historically, center hemodialysis patients in this metropolitan area received care at four centrally located facilities. In 1981, two new, independent facilities were constructed; a satellite of an existing unit was opened in 1983. The data obtained in this study demonstrated that end-stage renal disease (ESRD) patients generally did not change their mode of maintenance therapy, their treatment facility, or the location of their personal residence. When such changes occurred, they were rarely precipitated by a desire to reduce travel time to treatment. Furthermore, the opportunity to improve geographic access by transferring to a closer unit was perceived by patients to be viable only if they could retain their physician. It was concluded, therefore, that travel time to treatment is a relatively unimportant aspect of the chronic care of center hemodialysis patients in a metropolitan area.


An unusual complication of osteotome sinus floor elevation: benign paroxysmal positional vertigo.
Maxillary sinus floor elevation in cases of reduced vertical bone height in the posterior maxilla allows predictable implant placement. The osteotome sinus floor elevation (OSFE) technique has shorter healing and waiting times because the fixture can be placed in the implant recipient site simultaneously with the ridge augmentation. Implant site preparation is more comfortable for the patient when performed with spiral drills than with continuous malleting of the osteotomes. Membrane perforation is the most frequent complication with the OSFE technique; postoperative infection is rare. Benign paroxysmal positional vertigo (BPPV) may be a complication of OSFE and may cause stress if not identified correctly and managed properly. The available treatment options, diagnostic strategies and the pathophysiology of this unusual complication are discussed. The authors present a case in which intense BPPV developed during OSFE, focusing on dental and maxillofacial surgery as risk factors for this pathology.


Differential inhibition of protein translation machinery by curcumin in normal, immortalized, and malignant oral epithelial cells.
Curcumin has shown some promise in the prevention of oral carcinogenesis by mechanism(s) that are still not completely resolved. Messenger RNA translation is mediated in eukaryotes by the eIF4F complex composed of eukaryotic translation initiation factors eIF4E, eIF4G, and eIF4A. Overexpression of some of these components or the inactivation of initiation repressor proteins (4E-BP1) has been implicated in cancer development including oral carcinogenesis by affecting cell survival, angiogenesis, and tumor growth and invasion. In this study, we examined the possibility that curcumin affects the translational machinery differently in normal, immortalized normal, leukoplakia, and malignant cells. Curcumin treatment in vitro inhibited the growth of immortalized oral mucosa epithelial cells (NOM9-CT) and the leukoplakia cells (MSK-Leuk1s) as well as in the UMSCC22B and SCC4 cells derived from head and neck squamous cell carcinoma. Curcumin only exerted minor effects on the growth of normal oral epithelial cells (NOM9). In the immortalized, leukoplakia, and cancer cells, curcumin inhibited cap-dependent translation by suppressing the phosphorylation of 4E-BP1, eIF4G, eIF4B, and Mnk1, and also reduced the total levels of eIF4E and Mnk1. Our findings show that immortalized normal, leukoplakia, and malignant oral cells are more sensitive to curcumin and show greater modulation of protein translation machinery than the normal oral cells, indicating that targeting this process may be an important approach to chemoprevention in general and for curcumin in particular.


Prevalence and Recent Trends in Overweight, Obesity, and Severe Obesity among New Zealand Adolescents.
Around the world, there have been numerous reports of a leveling of the prevalence of obesity. Given that New Zealand has among the highest rates of child and adult obesity in the Organization for Economic Cooperation and Development (OECD), the aim of the current study was to document the prevalence of, and recent trends in, overweight, obesity, and severe obesity among adolescents in New Zealand. Data were collected as part of two nationally representative surveys in 2007 and 2012. In both surveys, a nationally representative group of students was selected to participate in the health and well-being surveys from a nationally representative sample of secondary schools. Across the two surveys, more than 17,000 students participated in the survey, which also included measured heights and weights. In 2012, nearly 40% of adolescents in New Zealand were overweight, obese, or severely obese. Between 2007 and 2012, there were no decreases in the prevalence of obesity for the general population or any demographic subgroup. However, the prevalence of obesity and severe obesity for Pacific young people increased significantly. Of note, the prevalence of severe obesity for Pacific young people increased from 9% in 2007 to 14% in 2012. Findings from the current study indicate the need for an urgent investment in obesity prevention, particularly to address the growing inequalities in obesity for Pacific young people.


Fatty acids modulate the composition of extracellular matrix in cultured human arterial smooth muscle cells by altering the expression of genes for proteoglycan core proteins.
In diabetes-associated microangiopathies and atherosclerosis, there are alterations of the extracellular matrix (ECM) in the intima of small and large arteries. High levels of circulating nonesterified fatty acids (NEFAs) are present in insulin resistance and type 2 diabetes. High concentrations of NEFAs might alter the basement membrane composition of endothelial cells. In arteries, smooth muscle cells (SMCs) are the major producers of proteoglycans and glycoproteins in the intima, and this is the site of lipoprotein deposition and modification, key events in atherogenesis. We found that exposure of human arterial SMCs to 100-300 micromol/albumin-bound linoleic acid lowered their proliferation rate and altered cell morphology. SMCs expressed 2-10 times more mRNA for the core proteins of the proteoglycans versican, decorin, and syndecan 4 compared with control cells. There was no change in expression of fibronectin and perlecan. The decorin glycosaminoglycan chains increased in size after exposure to linoleic acid. The ECM produced by cells grown in the presence of linoleic acid bound 125I-labeled LDL more tightly than that of control cells. Darglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma ligand, neutralized the NEFA-mediated induction of the decorin gene. This suggests that some of the NEFA effects are mediated by PPAR-gamma. These actions of NEFAs, if present in vivo, could contribute to changes of the matrix of the arterial intima associated with micro- and macroangiopathies.


Naturally occurring peer support through social media: the experiences of individuals with severe mental illness using YouTube.
Increasingly, people with diverse health conditions turn to social media to share their illness experiences or seek advice from others with similar health concerns. This unstructured medium may represent a platform on which individuals with severe mental illness naturally provide and receive peer support. Peer support includes a system of mutual giving and receiving where individuals with severe mental illness can offer hope, companionship, and encouragement to others facing similar challenges. In this study we explore the phenomenon of individuals with severe mental illness uploading videos to YouTube, and posting and responding to comments as a form of naturally occurring peer support. We also consider the potential risks and benefits of self-disclosure and interacting with others on YouTube. To address these questions, we used qualitative inquiry informed by emerging techniques in online ethnography. We analyzed n = 3,044 comments posted to 19 videos uploaded by individuals who self-identified as having schizophrenia, schizoaffective disorder, or bipolar disorder. We found peer support across four themes: minimizing a sense of isolation and providing hope; finding support through peer exchange and reciprocity; sharing strategies for coping with day-to-day challenges of severe mental illness; and learning from shared experiences of medication use and seeking mental health care. These broad themes are consistent with accepted notions of peer support in severe mental illness as a voluntary process aimed at inclusion and mutual advancement through shared experience and developing a sense of community. Our data suggest that the lack of anonymity and associated risks of being identified as an individual with severe mental illness on YouTube seem to be overlooked by those who posted comments or uploaded videos. Whether or not this platform can provide benefits for a wider community of individuals with severe mental illness remains uncertain.


Contact and contagion: Probability of transmission given contact varies with demographic state in bighorn sheep.
Understanding both contact and probability of transmission given contact are key to managing wildlife disease. However, wildlife disease research tends to focus on contact heterogeneity, in part because the probability of transmission given contact is notoriously difficult to measure. Here, we present a first step towards empirically investigating the probability of transmission given contact in free-ranging wildlife. We used measured contact networks to test whether bighorn sheep demographic states vary systematically in infectiousness or susceptibility to Mycoplasma ovipneumoniae, an agent responsible for bighorn sheep pneumonia. We built covariates using contact network metrics, demographic information and infection status, and used logistic regression to relate those covariates to lamb survival. The covariate set contained degree, a classic network metric describing node centrality, but also included covariates breaking the network metrics into subsets that differentiated between contacts with yearlings, ewes with lambs, and ewes without lambs, and animals with and without active infections. Yearlings, ewes with lambs, and ewes without lambs showed similar group membership patterns, but direct interactions involving touch occurred at a rate two orders of magnitude higher between lambs and reproductive ewes than between any classes of adults or yearlings, and one order of magnitude higher than direct interactions between multiple lambs. Although yearlings and non-reproductive bighorn ewes regularly carried M. ovipneumoniae, our models suggest that a contact with an infected reproductive ewe had approximately five times the odds of producing a lamb mortality event of an identical contact with an infected dry ewe or yearling. Consequently, management actions targeting infected animals might lead to unnecessary removal of young animals that carry pathogens but rarely transmit. This analysis demonstrates a simple logistic regression approach for testing a priori hypotheses about variation in the odds of transmission given contact for free-ranging hosts, and may be broadly applicable for investigations in wildlife disease ecology.


Characterization of size-dependent mechanical properties of tip-growing cells using a lab-on-chip device.
Quantification of mechanical properties of tissues, living cells, and cellular components is crucial for the modeling of plant developmental processes such as mechanotransduction. Pollen tubes are tip-growing cells that provide an ideal system to study the mechanical properties at the single cell level. In this article, a lab-on-a-chip (LOC) device is developed to quantitatively measure the biomechanical properties of lily (Lilium longiflorum) pollen tubes. A single pollen tube is fixed inside the microfluidic chip at a specific orientation and subjected to compression by a soft membrane. By comparing the deformation of the pollen tube at a given external load (compressibility) and the effect of turgor pressure on the tube diameter (stretch ratio) with finite element modeling, its mechanical properties are determined. The turgor pressure and wall stiffness of the pollen tubes are found to decrease considerably with increasing initial diameter of the pollen tubes. This observation supports the hypothesis that tip-growth is regulated by a delicate balance between turgor pressure and wall stiffness. The LOC device is modular and adaptable to a variety of cells that exhibit tip-growth, allowing for the straightforward measurement of mechanical properties.


Serum zinc and pneumonia in nursing home elderly.
Zinc plays an important role in immune function. The association between serum zinc and pneumonia in the elderly has not been studied. The objective was to determine whether serum zinc concentrations in nursing home elderly are associated with the incidence and duration of pneumonia, total and duration of antibiotic use, and pneumonia-associated and all-cause mortality. This observational study was conducted in residents from 33 nursing homes in Boston, MA, who participated in a 1-y randomized, double-blind, and placebo-controlled vitamin E supplementation trial; all were given daily doses of 50% of the recommended dietary allowance of essential vitamins and minerals, including zinc. Participants with baseline (n = 578) or final (n = 420) serum zinc concentrations were categorized as having low (<70 microg/dL) or normal (>or=70 microg/dL) serum zinc concentrations. Outcome measures included the incidence and number of days with pneumonia, number of new antibiotic prescriptions, days of antibiotic use, death due to pneumonia, and all-cause mortality. Compared with subjects with low zinc concentrations, subjects with normal final serum zinc concentrations had a lower incidence of pneumonia, fewer (by almost 50%) new antibiotic prescriptions, a shorter duration of pneumonia, and fewer days of antibiotic use (3.9 d compared with 2.6 d) (P <or= 0.004 for all). Normal baseline serum zinc concentrations were associated with a reduction in all-cause mortality (P = 0.049). Normal serum zinc concentrations in nursing home elderly are associated with a decreased incidence and duration of pneumonia, a decreased number of new antibiotic prescriptions, and a decrease in the days of antibiotic use. Zinc supplementation to maintain normal serum zinc concentrations in the elderly may help reduce the incidence of pneumonia and associated morbidity.


A Delphi study to develop practical diagnostic guidelines for visual stress (pattern-related visual stress).
Visual stress (VS) is characterised by symptoms of visual perceptual distortions and eyestrain when viewing text, symptoms that are alleviated by individually prescribed coloured filters. A recent review supports the existence of VS and its treatment, but noted that controversy remains, in part due to inconsistencies in the diagnosis of the condition. The present paper reviews the diagnostic criteria for VS in the literature and reports a Delphi analysis of the criteria currently used in clinical practice. Twenty-six eyecare practitioners were invited to participate in a Delphi study. They were selected because they were frequent prescribers of precision tinted lenses. In the first round they were sent a list of the indicators for which there is literature to suggest a relevance in the diagnosis of VS. The practitioners were invited to rank the indicators and add any additional criteria they use in diagnosis. In the second round a revised list was circulated, including items added from the responses in the first round. The respondents included optometrists, orthoptists and opticians. In the first round the response rate was 85%. Ninety-one percent of those who participated in the first round also responded in the second round. Strong indicators in the second round included the symptom of words moving when reading, voluntary use of an overlay for a prolonged period, improved performance of ≥15% with an overlay on the Wilkins Rate of Reading test, and an abnormally high score on the Pattern Glare Test. The strongest diagnostic criteria are combined in a diagnostic tool. This is proposed as a guide for clinical practice and further research.


An assessment of biodegradability of quaternary carbon-containing fragrance compounds: comparison of experimental OECD screening test results and in silico prediction data.
An assessment of biodegradability was carried out for fragrance substances containing quaternary carbons by using data obtained from Organisation for Economic Co-operation and Development (OECD) 301F screening tests for ready biodegradation and from Biowin and Catalogic prediction models. Despite an expected challenging profile, a relatively high percentage of common-use fragrance substances showed significant biodegradation under the stringent conditions applied in the OECD 301F test. Among 27 test compounds, 37% met the pass level criteria after 28 d, while another 26% indicated partial breakdown (≥20% biodegradation). For several compounds for which structural analogs were available, the authors found that structures that were rendered less water soluble by either the presence of an acetate ester or the absence of oxygen tended to degrade to a lesser extent compared to the primary alcohols or oxygenated counterparts under the test conditions applied. Difficulties were encountered when attempting to correlate experimental with in silico data. Whereas the Biowin model combinations currently recommended by regulatory agencies did not allow for a reliable discrimination between readily and nonbiodegradable compounds, only a comparably small proportion of the chemicals studied (30% and 63% depending on the model) fell within the applicability domain of Catalogic, a factor that critically reduced its predictive power. According to these results, currently neither Biowin nor Catalogic accurately reflects the potential for biodegradation of fragrance compounds containing quaternary carbons.


Solar water disinfection (SODIS): a review from bench-top to roof-top.
Solar water disinfection (SODIS) has been known for more than 30 years. The technique consists of placing water into transparent plastic or glass containers (normally 2L PET beverage bottles) which are then exposed to the sun. Exposure times vary from 6 to depending on the intensity of sunlight and sensitivity of the pathogens. Its germicidal effect is based on the combined effect of thermal heating of solar light and UV radiation. It has been repeatedly shown to be effective for eliminating microbial pathogens and reduce diarrhoeal morbidity including cholera. Since 1980 much research has been carried out to investigate the mechanisms of solar radiation induced cell death in water and possible enhancement technologies to make it faster and safer. Since SODIS is simple to use and inexpensive, the method has spread throughout the developing world and is in daily use in more than 50 countries in Asia, Latin America, and Africa. More than 5 million people disinfect their drinking water with the solar disinfection (SODIS) technique. This review attempts to revise all relevant knowledge about solar disinfection from microbiological issues, laboratory research, solar testing, up to and including real application studies, limitations, factors influencing adoption of the technique and health impact.


Deficient nonhomologous end-joining activity in cell-free extracts from Brca1-null fibroblasts.
BRCA1 ensures genomic stability, at least in part, through a functional role in DNA damage repair. BRCA1 interacts with the Rad50/Mre11/Nbs1 complex that occupies a central role in DNA double-strand break repair mediated by homologous recombination and nonhomologous end joining (NHEJ). NHEJ can be catalyzed by mammalian whole cell extract in a reaction dependent upon DNA ligase IV, Xrcc4, Ku70, Ku80, and DNA-PKcs. Here, we show that under identical cell-free reaction conditions, the addition of antibodies specific for BRCA1 and Rad 50 but not Rad51, inhibits end-joining activity. Cell extracts derived from Brca1-deficient mouse embryonic fibroblasts exhibit reduced end-joining activity independent of the endogenous protein amounts of DNA ligase IV, Ku80, and Ku70. The Brca1-dependent NHEJ activity predominates at the lower concentrations of Mg2+ (0.5 mM); elevated Mg2+ or Mn2+ concentrations (10 mM) dramatically increase overall end-joining activity and abrogates the requirement for Brca1, Xrcc4, and Ku70. The addition of partially purified BRCA1, in association with Rad50/Mre11/Nbs1 complex, complements the NHEJ deficiency of Brca1-null fibroblast extracts. These results suggest a role for Brca1 in NHEJ and in the maintenance of genome integrity.


Transcriptome profile analysis of flowering molecular processes of early flowering trifoliate orange mutant and the wild-type [Poncirus trifoliata (L.) Raf.] by massively parallel signature sequencing.
After several years in the juvenile phase, trees undergo flowering transition to become mature (florally competent) trees. This transition depends on the balanced expression of a complex network of genes that is regulated by both endogenous and environmental factors. However, relatively little is known about the molecular processes regulating flowering transition in woody plants compared with herbaceous plants. Comparative transcript profiling of spring shoots after self-pruning was performed on a spontaneously early flowering trifoliate orange mutant (precocious trifoliate orange, Poncirus trifoliata) with a short juvenile phase and the wild-type (WT) tree by using massively parallel signature sequencing (MPSS). A total of 16,564,500 and 16,235,952 high quality reads were obtained for the WT and the mutant (MT), respectively. Interpretation of the MPSS signatures revealed that the total number of transcribed genes in the MT (31,468) was larger than in the WT (29,864), suggesting that newly initiated transcription occurs in the MT. Further comparison of the transcripts revealed that 2735 genes had more than twofold expression difference in the MT compared with the WT. In addition, we identified 110 citrus flowering-time genes homologous with known elements of flowering-time pathways through sequencing and bioinformatics analysis. These genes are highly conserved in citrus and other species, suggesting that the functions of the related proteins in controlling reproductive development may be conserved as well. Our results provide a foundation for comparative gene expression studies between WT and precocious trifoliate orange. Additionally, a number of candidate genes required for the early flowering process of precocious trifoliate orange were identified. These results provide new insight into the molecular processes regulating flowering time in citrus.


The impact of community design and land-use choices on public health: a scientific research agenda.
The design of a community's built environment influences the physical and mental health of its residents. Because few studies have investigated this relationship, the Centers for Disease Control and Prevention hosted a workshop in May 2002 to help develop a scientific research agenda on these issues. Workshop participants' areas of expertise included physical activity, injury prevention, air pollution, water quality, urban planning, transportation, architecture, epidemiology, land use, mental health, social capital, housing, and social marketing. This report describes the 37 questions in the resulting research agenda. The next steps are to define priorities and obtain resources. The proposed research will help identify the best practices for designing new communities and revitalizing old ones in ways that promote physical and mental health.


Kangaroo mother care in the nursery.
Kangaroo mother care is becoming an integral part of the care of low birth weight infants worldwide. It provides economic savings to families and health care facilities and many physiologic and psychobehavioral benefits to mothers and infants, the most important of which is the promotion of successful breastfeeding. The benefits of breastfeeding, of human milk over formula, and of feeding from the breast per se, are beyond dispute, and so KMC should be actively promoted. The full impact of KMC on breastfeeding low birth weight infants is yet to be realized.


Synergistic Anticancer Effect of Tocotrienol Combined with Chemotherapeutic Agents or Dietary Components: A Review.
Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, apoptosis induction, antiangiogenesis, anti-metastasis, nuclear factor-κB suppression, and telomerase inhibition. Owing to a difference in the affinity of T3 and Toc for the α-tocopherol transfer protein, the bioavailability of orally ingested T3 is lower than that of Toc. Furthermore, cellular uptake of T3 is interrupted by coadministration of α-Toc in vitro and in vivo. Based on this, several studies are in progress to screen for molecules that can synergize with T3 in order to augment its potency. Combinations of T3 with chemotherapeutic drugs (e.g., statins, celecoxib, and gefitinib) or dietary components (e.g., polyphenols, sesamin, and ferulic acid) exhibit synergistic actions on cancer cell growth and signaling pathways. In this review, we summarize the current status of synergistic effects of T3 and an array of agents on cancer cells, and discuss their molecular mechanisms of action. These combination strategies would encourage further investigation and application in cancer prevention and therapy.


The optimal extent of resection for patients with stages I or II breast cancer treated with conservative surgery and radiotherapy.
The optimal extent of breast resection before irradiation for treatment of early breast cancer has not been defined. Increasing the size of the resection may decrease the risk of local recurrence but will also have an adverse impact on the cosmetic outcome. The 5-year likelihood of a recurrence of the tumor was analyzed in relation to the volume of resected breast tissue in 507 patients with infiltrating ductal carcinoma treated with conservative surgery and radiation therapy between 1968 and 1982. Patients were stratified by clinical T-stage and for each T-stage patients were divided into three groups of equal numbers based on the volume of excised tissue. All patients had at least a gross excision of the tumor and the extent of breast resection was determined at the discretion of the surgeon without knowledge of the histologic features of the tumor. The median follow-up time was 100 months. The 5-year actuarial recurrence rates were analyzed in relation to clinical T-stage (T1 or T2) and the presence or absence of an extensive intraductal component (EIC+ or EIC-). For patients with EIC+ tumors, the largest resections were associated with a substantially lower risk of recurrence in the breast than the smallest resections. This effect was seen both for T1 tumors (10% versus 29%, p = 0.07) and for T2 tumors (9% versus 36%, p = 0.04). For patients with EIC-tumors, recurrence rates were significantly lower than for EIC+ tumors and were not influenced by the volume of resection to the same degree as EIC+ tumors. In the absence of an EIC, recurrence rates for the largest and smallest resections were 0% and 9% (p = 0.02) for T1 tumors and 3% and 6% (p = NS) for T2 tumors. It is concluded that a limited breast resection is acceptable for an EIC- tumor but that a more extensive resection is required for an EIC+ tumor. These results stress the importance of assessing the presence or absence of an EIC in determining the optimal extent of breast resection required before radiation therapy.


HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects.
Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted. Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.


Creation of Bone and Soft Tissue in Postmaxillectomy Patients Using Curvilinear Transport Distraction Osteogenesis.
Large surgical defects in the maxilla due to trauma or tumor are usually reconstructed with revascularized-free fibula flaps (RFFF). In the past, the use of curvilinear transport distraction osteogenesis (CTDO) has been shown to be an efficacious way in closing large defects in the maxilla, but it had limitations which have now been overcome by the present development. The present distractor is an improvement upon the previous three prototypes and employs the concept of tetrafocal distraction by means of hybridizing the bone with the tooth in the transport disc segment. This article aims to prove that tetrafocal distraction provides a viable alternative to the RFFF. In a prospective cohort study of six postmaxillectomy patients, the method of CTDO was applied and investigated to ascertain the outcome. The regenerate bone was compared with the parent bone, using a new maxillary transport distractor. A linear bicortical fracture was created in the maxilla in a vertical direction (segmentally) to develop a mobile, vascularized transport disk. This transport disk underwent further subdivision to produce the concept of tetrafocal distraction. After osseointegration of the dental implants, prosthetic rehabilitation of the dentition was successful. The authors report the successful outcome of two of the six cases subjected to CTDO to treat defects ranging from 25 mm (using bifocal distraction) to 80 mm along a curved trajectory (using tetrafocal distraction). The production of curvilinear bone and soft tissue along a horizontal plane has been demonstrated. From a clinical perspective, the new alveolar bone achieved the correct width and height to create a physiological vestibule and an esthetic zone for dental implants. In addition, the shape of the palatal vault is also reconstituted. The tetrafocal method of the CTDO is a reliable method of maxillary reconstruction.


Radiographic patterns of periodontitis in cats: 147 cases (1998-1999).
To determine patterns of alveolar bone loss (periodontitis) and other lesions evident on full-mouth survey radiographs of cats. Retrospective study. 147 cats. Full-mouth radiographs were evaluated for evidence and severity of alveolar bone loss, odontoclastic resorption lesions (ORL), retained roots, missing teeth, signs of endodontic disease secondary to periodontitis, and apical resorption. 106 (72%) cats had some degree of periodontitis, 100 (68%) were missing teeth, 98 (67%) had ORL, 78 (53%) had expansion of the buccal alveolar bone at 1 or more canine teeth, 75 (51%) had retained roots, 48 (33%) had apical resorption, and 12 (8%) had signs of endodontic disease secondary to periodontitis. Cats < 4 years old were not significantly more likely than the general population to have normal alveolar bone height. Prevalence of ORL increased with age, but cats > or =13 years old were less likely than the general population to have moderate or severe generalized periodontitis. Purebred cats were not significantly more likely to have periodontitis or ORL than mixed-breed cats. Results suggest that periodontitis is common in cats and that horizontal bone loss is the most common radiographic pattern of alveolar bone loss. Purebred cats were not more likely than mixed-breed cats to have ORL or periodontitis, but when they did have periodontitis, it was more likely to be moderate to severe. Cats with ORL were less likely than cats without ORL to have normal alveolar bone height and more likely to have severe focal vertical bone loss.


TNFα decreases mitochondrial movement in human airway smooth muscle.
In airway smooth muscle (ASM) cells, excitation-contraction coupling is accomplished via a cascade of events that connect an elevation of cytosolic Ca2+ concentration ([Ca2+]cyt) with cross-bridge attachment and ATP-consuming mechanical work. Excitation-energy coupling is mediated by linkage of the elevation of [Ca2+]cyt to an increase in mitochondrial Ca2+ concentration, which in turn stimulates ATP production. Proximity of mitochondria to the sarcoplasmic reticulum (SR) and plasma membrane is thought to be an important mechanism to facilitate mitochondrial Ca2+ uptake. In this regard, mitochondrial movement in ASM cells may be key in establishing proximity. Mitochondria also move where ATP or Ca2+ buffering is needed. Mitochondrial movement is mediated through interactions with the Miro-Milton molecular complex, which couples mitochondria to kinesin motors at microtubules. We examined mitochondrial movement in human ASM cells and hypothesized that, at basal [Ca2+]cyt levels, mitochondrial movement is necessary to establish proximity of mitochondria to the SR and that, during the transient increase in [Ca2+]cyt induced by agonist stimulation, mitochondrial movement is reduced, thereby promoting transient mitochondrial Ca2+ uptake. We further hypothesized that airway inflammation disrupts basal mitochondrial movement via a reduction in Miro and Milton expression, thereby disrupting the ability of mitochondria to establish proximity to the SR and, thus, reducing transient mitochondrial Ca2+ uptake during agonist activation. The reduced proximity of mitochondria to the SR may affect establishment of transient "hot spots" of higher [Ca2+]cyt at the sites of SR Ca2+ release that are necessary for mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter.


Evaluation of the South Korean national long-term care insurance-funded cognitive function training programme for older people with mild dementia.
despite the extensive literature on the effectiveness of cognitive training, its effectiveness has not been demonstrated within a population-based long-term care system. To provide cognitive training services to older people with mild dementia, Korea introduced a special dementia rating, as a long-term care grades, in the national long-term care insurance in July 2014. These services are only offered to those with the special dementia rating. This study evaluated the national long-term care insurance-funded cognitive function training programme for older people with mild dementia. data were derived from the Korean National Health Insurance Elderly Cohort database between 2008 and 2015. We compared changes in function between the intervention (n = 352) and control (n = 1952) groups before (2014) and after (2015) introduction of the cognitive function training programme. Difference-in-differences analysis was performed, to compare changes in each score between the intervention and control groups before and after introduction of the cognitive function training programme. introduction of the cognitive function training programme was associated with significantly less cognitive function decline in the intervention group than in the control groups (β = -3.39; standard errors [SE] = 1.14; P = 0.003). A subgroup analysis revealed that this effect increased in subjects in the youngest group, low income bracket, who had a primary caregiver, who were supported in multiple activities of daily living by the primary caregiver, or who were not living alone. introduction of the cognitive function training programme was associated with positive effects on cognitive function.


The alpha-like scorpion toxin BmK I enhances membrane excitability via persistent sodium current by preventing slow inactivation and deactivation of rNav1.2a expressed in Xenopus Oocytes.
BmK I is classified as alpha-like scorpion toxin that specifically binds the voltage-gated sodium channels via receptor site-3. Previous results showed BmK I induced epileptiform responses in rats via intra-hippocampal injection, but the mechanism has yet to be clarified. In this study, using two-electrode voltage/current clamp technique, we determined the effects of BmK I on rNav1.2a expressed in Xenopus oocytes. The results showed that BmK I prevented the development of slow inactivation of rNav1.2a from the open-state and enhanced the persistent sodium current (I(NaP)) at suprathreshold potentials in concentration-dependence, whereas it hardly affected the fast inactivation. BmK I was also able to augment the subthreshold I(NaP) at high concentrations (>100nM) with disruption of the open-state deactivation. The increased I(NaP) accelerated the firing frequency in the oocytes that fired repetitively after electrode punctures, as well as raised the baseline potential and induced bursting of spikes in the quiescent oocytes. These results demonstrated that BmK I could target rNav1.2a and induce the I(NaP) by preventing the development of slow inactivation and deactivation from the open-state, leading to the enhancement of membrane excitability, which may be involved in the BmK I-induced epilepsy.


The use of nonpharmacologic techniques to prevent postoperative nausea and vomiting: a meta-analysis.
We assessed the efficacy of nonpharmacologic techniques to prevent postoperative nausea and vomiting (PONV) by systematic review. These studies included acupuncture, electroacupuncture, transcutaneous electrical nerve stimulation, acupoint stimulation, and acupressure. Of the 24 randomized trials retrieved by a search of articles indexed on the MEDLINE and EMBASE databases (1980-1997), 19 were eligible for meta-analysis. The primary outcomes were the incidence of nausea, vomiting, or both 0-6 h (early efficacy) or 0-48 h (late efficacy) after surgery. The pooled relative risk (RR) and numbers needed to treat (NNT) were calculated. In children, no benefit was found. Some results in adults were significant. Nonpharmacologic techniques were similar to antiemetics in preventing early vomiting (RR = 0.89 [95% confidence interval 0.47-1.67]; NNT = 63 [10-infinity]) and late vomiting (RR = 0.80 [0.35-1.81]; NNT = 25 [5-infinity]) in adults. Nonpharmacologic techniques were better than placebo at preventing early nausea (RR = 0.34 [0.20-0.58]; NNT = 4 [3-6]) and early vomiting in adults (RR = 0.47 [0.34-0.64]; NNT = 5 [4-8]). Nonpharmacologic techniques were similar to placebo in preventing late vomiting in adults (RR = 0.81 [0.46-1.42]; NNT = 14 [6-infinity]). Using nonpharmacologic techniques, 20%-25% of adults will not have early PONV compared with placebo. It may be an alternative to receiving no treatment or first-line antiemetics. This systematic review showed that nonpharmacologic techniques were equivalent to commonly used antiemetic drugs in preventing vomiting after surgery. Nonpharmacologic techniques were more effective than placebo in preventing nausea and vomiting within 6 h of surgery in adults, but there was no benefit in children.


Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives.
In prospective studies of acute uncomplicated, multidrug-resistant falciparum malaria on the western border of Thailand, the oral artemisinin derivatives were used alone in the treatment of 836 patients (artesunate 630, artemether 206), were combined with mefloquine (15-25 mg base/kg) in 2,826 patients, and mefloquine alone was used in 1,303 patients. The combined regimens of mefloquine plus an artemisinin derivative were associated with more side effects than those with an artemisinin derivative alone; acute nausea (31% versus 16%), vomiting (24% versus 11%), anorexia (51% versus 34%), and dizziness (47% versus 15%) (P < 0.001). Oral artesunate and artemether alone were very well tolerated. There was no difference in the incidence of possible adverse effects between the two drugs, and no evidence that either derivative caused allergic reactions, neurologic or psychiatric reactions, or cardiovascular or dermatologic toxicity. Blackwater fever occurred in three patients treated with mefloquine plus artesunate regimens. Oral artesunate and artemether are safe and well tolerated antimalarial drugs.


Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair.
Increased leukocyte elastase activity in mice lacking secretory leukocyte protease inhibitor (SLPI) leads to impaired wound healing due to enhanced activity of TGFbeta and perhaps additional mechanisms. Proepithelin (PEPI), an epithelial growth factor, can be converted to epithelins (EPIs) in vivo by unknown mechanisms with unknown consequences. We found that PEPI and EPIs exert opposing activities. EPIs inhibit the growth of epithelial cells but induce them to secrete the neutrophil attractant IL-8, while PEPI blocks neutrophil activation by tumor necrosis factor, preventing release of oxidants and proteases. SLPI and PEPI form complexes, preventing elastase from converting PEPI to EPIs. Supplying PEPI corrects the wound-healing defect in SLPI null mice. Thus, SLPI/elastase act via PEPI/EPIs to operate a switch at the interface between innate immunity and wound healing.


Review: steady and pulsed pedestals, the how and why of post-receptoral pathway separation.
In the mid-1990s, the Pokorny and Smith research group began a series of psychophysical experiments with the aim of separately measuring magnocellular (MC)- and parvocellular (PC)-pathway mediated achromatic contrast discrimination. Three paradigms provide complementary information: The pulsed-pedestal paradigm reveals PC contrast gain, the steady-pedestal paradigm reveals steady-state MC-pathway sensitivity, and the pedestal-Δ-pedestal paradigm reveals MC contrast gain. Further studies investigated the temporal and spatial summation properties of the underlying mechanisms and extended the work to include measures of spatial resolution, chromatic contrast discrimination, the detection and identification of stimulus polarity, and the inferred retinal mechanisms mediating illusory distortions. Other laboratories have also applied the methods to the study of normal and clinically impaired vision. This review describes the pedestal methodologies, how they relate to physiology, and how they have been and should be employed.


Human papilloma virus 16 E6 oncoprotein associated with p53 inactivation in colorectal cancer.
To investigate the association between human papilloma virus (HPV) infection and colorectal cancer. Sixty-nine patients with pathologically confirmed primary colorectal cancer including 6 stage I, 24 stage II, 21 stage III, and 18 stage IV patients were enrolled in this study to investigate whether HPV 16 could be involved in colorectal tumorigenesis. Nested-polymerase chain reaction (nested-PCR) was used to detect HPV16 DNA in colorectal tumor tissues and further confirmed by in situ hybridization (ISH). In addition, immunohistochemistry analysis was performed to examine the E6 oncoprotein in colorectal tumors. To verify whether E6 could inactivate the p53 transcriptional function, the levels of p21 and Mdm2 mRNA expression were evaluated by real-time reverse transcription (RT)-PCR. Of the 69 colorectal tumors, HPV16 DNA was detected in 11 (16%) by nested-PCR, and HPV16 DNA was present in 8 of the 11 (73%) tumors which was confirmed by ISH. The presence of HPV16 DNA in colorectal tumors was not associated with patients' clinical parameters including age, gender, smoking status, tumor site; however, HPV16 infection was more common in stage I patients than in late-stages patients (II, III and IV). We next asked whether HPV16 infection could be linked with colorectal cancer development. Immunohistochemical data indicated that 8 of the 11 HPV16 DNA-positive tumors had E6 oncoprotein expression. Moreover, we also observed that the adjacent normal tissues including endothelial cells, lymphocytes, fibroblasts, and gland cells in E6-positive tumors had E6 oncoprotein expression. In addition, 3 of the 4 (75%) E6-positive tumors carrying p53 wild-type had negative immunostaining, but one tumor had less p53 immunostaining. We further examined whether E6-positive and/or p53 mutated tumors reduce p53 transcriptional activity. Real-time RT-PCR analysis indicated that p21 and mdm2 mRNA expression levels in E6/p53-wildtype tumors were significantly lower than in their adjacent normal tissues; as expected, E6-positive/p53-mutated tumors had lower p21 and mdm2 mRNA expression levels compared with their adjacent normal tissues. These results clearly indicate that the E6 oncoprotein expressed in p53 wildtype tumors may reduce p21 and mdm2 expression via p53 inactivation. These results suggest that HPV16 infection may be involved in a subset of colorectal cancer, and we suggest that the transmission of HPV to the colon and rectum might occur through peripheral blood lymphocytes.


A genetic polymorphism in the constant region of rabbit b4 kappa chains.
Amino acid sequence analysis of a b4 light chain from a rabbit homogeneous antistreptococcal antibody revealed the presence of two amino acid substitutions in the constant region not previously reported for these positions. These interchanges, consisting of serine for alanine at position 121 and leucine for glutamine at position 124, were also present in about 30% of the pooled b4 light chains isolated from pooled IgG from the rabbit (4539) that produced the homogeneous antibody. In addition, these interchanges (b4var) were found, always at the same levels, in varying percentages in nonimmune or early immune bleedings from related rabbits in this pedigreed family and could be traced for five generations. The inheritance pattern of b4var was consistent with autosomal codominant inheritance.


An expanded view of bacterial DNA replication.
A protein-interaction network centered on the replication machinery of Bacillus subtilis was generated by genome-wide two-hybrid screens and systematic specificity assays. The network consists of 91 specific interactions linking 69 proteins. Over one fourth of the interactions take place between homologues of proteins known to interact in other organisms, indicating the high biological significance of the other interactions we report. These interactions provide insights on the relations of DNA replication with recombination and repair, membrane-bound protein complexes, and signaling pathways. They also lead to the biological role of unknown proteins, as illustrated for the highly conserved YabA, which is shown here to act in initiation control. Thus, our interaction map provides a valuable tool for the discovery of aspects of bacterial DNA replication.


The 10-Min Holistic Self-Care for Patients with Breast Cancer-Related Lymphedema: Pilot Randomized Controlled Study.
About 20% of patients with breast cancer are likely to develop breast cancer-related lymphedema (BCRL) following an axillary clearance, and BCRL can be refractory or irreversible to treatment. The aim of this pilot randomized controlled study was to evaluate the effectiveness of a 10-min holistic self-care program for patients with BCRL in Japan. The intervention group (n = 22) practiced the BCRL self-care program including 1) modified Japanese Radio Taiso (Rajio Taiso, national calisthenics in Japan), 2) gentle arm exercises combined with deep breathing, 3) central lymphatic drainage, and 4) skin care using a traditional lymphatic drainage technique daily for 6 months, while the control group (n = 21) received usual care from their hospitals. There was significant group*time interaction in the relative edema volume and relative volume change of the hand, with the intervention group having the better outcome. The intervention group showed significant improvement in transepidermal water loss as well as the mental health component summary score of the SF-8, most of BCRL-related symptoms, self-care time and score, frequencies of exercise, self-lymphatic drainage and skin care, and perceived adherence and effectiveness to self-care, although we were unable to exclude the possibility of the Hawthorne effect. Notably, even in the control group, the self-care was similarly increased, but the significant improvements were detected only in transepidermal water loss on the forearm and upper arm, pain and coldness. In conclusion, the patients who practiced the holistic BCRL self-care for 6 months have shown greater improvement.


Stable 8-hydroxyquinolinate-based podates as efficient sensitizers of lanthanide near-infrared luminescence.
New polydentate ligands (e.g., Tsox and TsoxMe) have been synthesized to take advantage of the chelating effect of bidentate 8-hydroxyquinolinate subunits connected to a N,N,N',N'-tetraaminopropyl-1,2-ethylenediamine framework and with the aim of sensitizing the NIR luminescence of Nd(III) and Yb(III) ions. Ten pK(a)'s have been determined and the interaction between the ligands and Ln(III) ions in dilute aqueous solution has been probed both by potentiometric and spectrophotometric titrations. These studies have been mostly performed with the Eu(III) ion, which is in the middle of the lanthanide series, and extended to other ions (La(III), Er(III), Lu(IIII)). Stable complexes with Ln(III) ions are formed (pLn in the range of 14-16), the four chromophoric units being coordinated to the metal center, exploiting the entropic effect generated by the anchor. The monometallic complexes [Ln(H(2)L)](3)(-) exist as the major species at physiological pH regardless of the lanthanide used. Lifetime determinations of the Nd((4)F(3/2)) and Yb((2)F(5/2)) excited levels in both H(2)O and D(2)O at buffered pH point to the absence of water molecules bound in the inner coordination sphere of the Ln(III). Photophysical properties of the free ligands and of their lanthanide complexes have been investigated in buffered aqueous solutions both at room temperature and 77 K. The low-energy triplet state makes energy transfers from the ligand to the metal ions possible; this leads to a sizable sensitization of the Nd(III)- or Yb(III)-centered luminescence ( = 0.02% and = 0.18%) for Tsox chelates. Methylation of the amide functions removes the quenching mechanism induced by the proximate N-H vibrations and increases both the lifetimes and quantum yields of the TsoxMe chelates ( = 0.04% and = 0.37%). In fact, TsoxMe yields one of the most luminescent Yb(III) compounds known in water, and this ligand appears to be suitable for the development of NIR probes for bioanalyses.


Epigenetic mechanisms, trauma, and psychopathology: targeting chromatin remodeling complexes.
Environmental pressure affects the genotype throughout different epigenetic processes. There is currently ample evidence on the role of epigenetics in developing various mental disorders. A burden of environmental pressure, such as psychological trauma, and its influence on genotype can lead to a variety of psychopathologies. Thus, this study focuses on the epigenetic activity of the complex protein machinery operating on chromatin - the ATP-dependent chromatin remodeling complexes. Although there are several recent studies on the molecular structure, functions, and taxonomy of ATP-dependent chromatin remodeling complexes, the focus of this paper is to highlight the importance of those 'protein machines' in developing psychiatric disorders. Data were obtained from human preclinical and clinical studies. The results of this review indicate an importance of ATP-dependent chromatin remodeling complexes in the interaction between environmental factors, including traumatic events, and genetic vulnerability to stress. Several studies indicate that ATP-dependent chromatin remodeling complexes play a crucial role in the development and consolidation of memory, in neurodevelopmental processes, and in etiology depressive-like behavior. Thus, the activity of those 'protein machines' emerges as a key factor in the pathophysiology of various psychiatric diseases. It can also be concluded that the limitations of clinical studies may be explained by inappropriate laboratory methods and research paradigms due to the delayed timeframe of biochemical responses to environmental stimuli. Future research in this field may enable a better understanding of the pathophysiology of psychiatric diseases and contribute to the development of novel molecular treatment targets.


LILY-lipidome isotope labeling of yeast: in vivo synthesis of 13C labeled reference lipids for quantification by mass spectrometry.
Quantification is an essential task in comprehensive lipidomics studies challenged by the high number of lipids, their chemical diversity and their dynamic range of the lipidome. In this work, we introduce lipidome isotope labeling of yeast (LILY) in order to produce (non-radioactive) isotopically labeled eukaryotic lipid standards in yeast for normalization and quantification in mass spectrometric assays. More specifically, LILY is a fast and efficient in vivo labeling strategy in Pichia pastoris for the production of 13C labeled lipid library further paving the way to comprehensive compound-specific internal standardization in quantitative mass spectrometry based assays. More than 200 lipid species (from PA, PC, PE, PG, PI, PS, LysoGP, CL, DAG, TAG, DMPE, Cer, HexCer, IPC, MIPC) were obtained from yeast extracts with an excellent 13C enrichment >99.5%, as determined by complementary high resolution mass spectrometry based shotgun and high resolution LC-MS/MS analysis. In a first proof of principle study we tested the relative and absolute quantification capabilities of the 13C enriched lipids obtained by LILY using a parallel reaction monitoring based LC-MS approach. In relative quantification it could be shown that compound specific internal standardization was essential for the accuracy extending the linear dynamic range to four orders of magnitude. Excellent analytical figures of merit were observed for absolute quantification for a selected panel of 5 investigated glycerophospholipids (e.g. LOQs around 5 fmol absolute; typical concentrations ranging between 1 to 10 nmol per 108 yeast cell starting material; RSDs <10% (N = 4)).


Patient activation and functional recovery in persons undergoing spine surgery.
Despite advances in surgical techniques, outcomes after spine surgery are highly variable. Recent research has highlighted the importance of individuals participating in, and taking responsibility for, their health and recovery. Patient activation, defined as an individual's propensity to engage in adaptive health behaviors leading to improved health outcomes, has been identified as a potentially important factor in this process. Our goal was to determine the association between preoperative patient activation and functional recovery after lumbar spine surgery. We prospectively followed sixty-five consecutive patients undergoing lumbar spine surgery from August 2005 through May 2006. Patient activation was assessed preoperatively as one of four stages. We assessed pain intensity, disability, and functional status preoperatively and postoperatively with use of a numeric rating scale for pain, the Oswestry Disability Index, and the Medical Outcomes Study Short Form-12 (version 2). Comparisons were made for disability and functional status as a function of patient activation. Repeated-measures linear regression models were used to test the association between patient activation and functional recovery over time. Preoperatively, we rated participant activation as low (Stage I, fifteen patients), high (Stage IV, sixteen patients), and intermediate (Stage II, twelve patients; Stage III, twenty-two patients; total, thirty-four patients). Overall, pain and disability decreased after surgery (p < 0.05). Stage-IV participants experienced a greater degree of decrease in pain (p = 0.049) and disability (p = 0.035) than did Stage-I participants. Overall, physical and mental health improved after surgery (p < 0.05), but only physical health differed according to patient activation, with a significantly smaller improvement in Stage-I participants than in Stage-IV participants (p = 0.044). High patient activation was associated with better recovery after surgery. Increased patient activation may lead to improved functional recovery through increased physical therapy adherence after spine surgery in adults.


Country of birth, country of residence, and menopausal transitions and symptoms: British birth cohort and Australian Longitudinal Study on Women's Health.
To explore endocrine-related and general symptoms among three groups of middle-aged women defined by country of birth and country of residence, in the context of debates about biological, cultural and other factors in menopause. British-born women participating in a British birth cohort study (n=1,362) and age-matched Australian-born (n=1,724) and British-born (n=233) Australian women selected from the Australian Longitudinal Study on Women's Health (ALSWH) responded to two waves of surveys at ages 48 and 50. Australian-Australian and British-Australian women report reaching menopause later than British-British women, even after accounting for smoking status and parity. Hormone replacement therapy (HRT) use was lower and hysterectomy was more common among both Australian groups, probably reflecting differences in health services between Britain and Australia. The Australian-Australian and British-Australian groups were more likely to report endocrine-related symptoms than the British-British group, even after adjusting for menopausal status. British-British women were more likely to report some general symptoms. Symptom reporting is high among Australian and British midlife women and varies by country of residence, country of birth and menopausal status. The data do not support either a simple cultural or a simple biological explanation for differences in menopause experience.


Implementation of Mass Cytometry as a Tool for Mechanism of Action Studies in Inflammatory Bowel Disease.
Novel therapeutics for inflammatory bowel disease (IBD) are under development, yet mechanistic readouts at the tissue level are lacking. Techniques to assess intestinal immune composition could represent a valuable tool for mechanism of action (MOA) studies of novel drugs. Mass cytometry enables analysis of intestinal inflammatory cell infiltrate and corresponding molecular fingerprints with unprecedented resolution. Here, we aimed to optimize the methodology for isolation and cryopreservation of cells from intestinal tissue to allow for the potential implementation of mass cytometry in MOA studies. We investigated key technical issues, including minimal tissue requirements, cell isolation protocols, and cell storage, using intestinal biopsies and peripheral blood from healthy individuals. High-dimensional mass cytometry was employed for the analyses of biopsy-derived intestinal cellular subsets. Dithiothreitol and mechanical dissociation decreased epithelial cell contamination and allowed for isolation of adequate cell numbers from 2 to 4 colonic or ileal biopsies (6 × 104±2 × 104) after a 20-minute collagenase digestion, allowing for reliable detection of most major immune cell subsets. Biopsies and antibody-labeled mononuclear cells could be cryopreserved for later processing and acquisition (viability > 70%; P < 0.05). Mass cytometry represents a unique tool for deep immunophenotyping intestinal cell composition. This technique has the potential to facilitate analysis of drug actions at the target tissue by identifying specific cellular subsets and their molecular signatures. Its widespread implementation may impact not only IBD research but also other gastrointestinal conditions where inflammatory cells play a role in pathogenesis.


Temporary monocular occlusion facilitates binocular fusion during rivalry.
A few hours of monocular patching temporarily enhances the deprived eye's contribution to binocular vision, constituting a form of adult brain plasticity. Although the mechanism for this plasticity is currently unknown, several imaging studies present evidence that monocular deprivation achieves its effects by changing excitatory-inhibitory balance in the visual cortex. Much of the past work on adult monocular patching utilized binocular rivalry to quantify the patching-induced shift in perceptual eye dominance, extracting periods of exclusive visibility (in which one eye's signal is suppressed from perception) to assess each eye's contribution to binocular vision while overlooking the occurrence of mixed visibility (in which information from both eyes is combined). In this paper, we discuss two experiments to investigate the effects of short-term monocular occlusion on the relative predominance of mixed and exclusive percepts during binocular rivalry. In addition to the known perceptual eye-dominance shift, we hypothesized patching would also increase the perception of mixtures during rivalry due to deprivation-induced changes in excitatory-inhibitory balance. Our data point to two previously unknown effects of monocular deprivation: (a) a significant increase in the overall fraction and median duration of mixed visibility during rivalry that is detectable up to at least an hour after removing the patch and (b) the overall fraction of superimposition; rather than piecemeal, mixed percepts are specifically enhanced after monocular deprivation. In addition to strengthening the contribution of the deprived eye, our results show that temporary monocular patching enhances the visibility of fused binocular percepts, likely the result of attenuated interocular inhibition.


Developmental regulation of rat brain/Hep G2 glucose transporter gene expression.
The developmental regulation of rat brain-derived/Hep G2 glucose transporter gene expression was studied by means of Northern blot hybridization, using a rat brain glucose transporter cDNA probe, in order to directly quantify steady state glucose transporter mRNA levels. The results obtained showed different tissue-specific patterns of glucose transporter mRNA levels during ontogenesis; while in brain there was a sustained increase in the levels of the message from 20 days embryogenesis until 50 days postnatal, other organs such as heart, lung, liver, and muscle expressed maximal levels of the glucose transporter mRNA in 20-day fetuses and 1-day neonates, decreasing subsequently to very low levels. The relative expression of the glucose transporter mRNA in the different tissues, at both fetal and adult stages, was analyzed using a solution hybridization-RNase protection assay. This approach revealed that, while the heart expresses the highest levels of glucose transporter mRNA at 20 days of fetal life, the brain shows the highest levels at the adult stage. These results indicate a tissue-specific ontogenic pattern of glucose transporter gene expression, suggesting a developmental role for this glucose transporter gene product.


Dual effects of β3 integrin subunit expression on human pancreatic cancer models.
pancreatic cancer, the fifth leading cause of adult cancer death in Western countries, lacks early detection, and displays significant dissemination ability. Accumulating evidence shows that integrin-mediated cell attachment to the extracellular matrix induces phenotypes and signaling pathways that regulate tumor cell growth and migration. in view of these findings, we examined the role of β3 in pancreatic cancer by generating two stable β3-expressing pancreatic human cell lines and characterizing their behavior in vitro and in vivo. transduction of β3 selectively augmented the functional membrane αvβ3 integrin levels, as evident from the enhanced adhesion and migration abilities related to active Rho GTPases. No effects on in vitro anchorage-dependent growth, but higher anoikis were detected in β3-overexpressing cells. Moreover, tumors expressing β3 displayed reduced growth. Interestingly, treatment of mice with an αv-blocking antibody inhibited the growth of β3-expressing tumors to a higher extent. our results collectively support the hypothesis that αvβ3 integrin has dual actions depending on the cell environment, and provide additional evidence on the role of integrins in pancreatic cancer, which should eventually aid in improving prediction of the effects of therapies addressed to modulate integrin activities in these tumors.